Flavonoids are one of the most numerous and best-studied groups of plant polyphenols. The flavonoids consist of a large group of low-molecular weight polyphenolic substances naturally occurring in fruits and vegetables, and are an integral part of the human diet. Dried green tea leaves can contain as much as 30% flavonoids by weight, including a high percentage of flavonoids known as catechins (flavan-3-ol derivatives or catechin-based flavonoids), including (−)-epicatechin, (−)-epigallocatechin, (+)-catechin, (−)-epicatechin gallate and (−)-epigallocatechin gallate.
In recent years, these green tea catechins have attracted much attention because they have been recognized to have biological and pharmacological properties, including antibacterial, antineoplastic, anti-thrombotic, vasodilatory, antioxidant, anti-mutagenic, anti-carcinogenic, hypercholesterolemic, antiviral and anti-inflammatory properties, which have been demonstrated in numerous human, animal and in vitro studies (Jankun J., et al. Nature 387, 561 (1997); Bodoni A. et al. J. Nutr. Biochem. 13, 103-111 (2002); Nakagawa K. et al. J. Agric. Food Chem. 47, 3967-3973 (1999)). These biological and pharmacological properties are potentially beneficial in preventing diseases and protecting the stability of the genome. Many of the beneficial effects of catechins are thought to be linked to the antioxidant actions of the catechins (Terao J., et al. Arch. Biochem. Biophys. 308, 278-284 (1994)). Among the catechins, (−)-epigallocatechin gallate (EGCG), which is a major component of green tea, is thought to have the highest activity, possibly due to the trihydroxy B ring and the gallate ester moiety at the C3 position (Isemura M., et al. Biofactors 13, 81-85 (2000); Ikeda I., et al. J. Nutr. 135, 155 (2005); Lill G., et al. FEBS Letters 546, 265-270 (2003); Sakanaka S. and Okada Y. J. Agric. Food Chem. 52, 1688-1692 (2004); Yokozawa T., et al., J. Agric. Food Chem. 48, 5068-5073 (2000)).
In general, the activity half-life of flavonoids is limited to a few hours inside the body; metabolism of these compounds has not yet been established. Despite the favorable anti-oxidation and anti-cancer properties of the catechins including EGCG, it is impractical to achieve a therapeutic level of this compound in the body by directly ingesting a large amount of green tea, due to the inherent volume constraint. That is, in order to obtain a therapeutic or pharmacological benefit from flavonoids through diet alone, it would be necessary to ingest an amount of food and beverage that is larger than is practical to consume. Moreover, pro-oxidant activity has been reported for several flavonoids including EGCG, making ingesting crude green tea directly a less effective means of delivering EGCG (Yen G. C., et al. J. Agric. Food Chem. 45, 30-34 (1997); Yamanaka N., et al. FEBS Lett. 401, 230-234 (1997); Roedig-Penman A. and Gordon M. H. J. Agric. Food Chem. 1997, 45, 4267-4270).
On the other hand, a relatively high-molecular fraction of extracted plant polyphenols (procyanidins) and synthetically oligomerized (+)-catechin and rutin have been reported to exhibit enhanced physiological properties such as antioxidant and anti-carcinogenic activity compared to low-molecular weight flavonoids, (Zhao J., et al. Carcinogenesis, 1999, 20, 1737-1745; Ariga T. and Hamano M. Agric. Biol. Chem. 54, 2499-2504 (1990); Chung J. E., et al. Biomacromolecules 5, 113-118 (2004); Kurisawa M., et al. Biomacromolecules 4, 1394-1399 (2003); Hagerman A. E., et al. J. Agric. Food Chem. 46, 1887 (1998)) and without pro-oxidant effects (Hagerman A. E., et al. J. Agric. Food Chem. 46, 1887 (1998); Li C. and Xie B. J. Agric. Food Chem. 48, 6362 (2000)). However, neither naturally occurring nor synthesized high molecular weight flavonoids are expected to be absorbed and transported to other tissues after ingestion, since these compounds are typically large, form strong complexes with proteins and are resistant to degradation (Zhao J., et al. Carcinogenesis, 1999, 20, 1737-1745).
In cases of flavonoids consumed via oral intake of foods and beverages, the flavonoids may play a role as antioxidants to protect the digestive tract from oxidative damage during digestion. However, flavonoids can be expected to remain only in the digestive tract and thus their beneficial physiological activities are not likely to be utilized to other tissues. Moreover, their strong hydrophobicity as well as their tendency to form complexes with proteins makes parenteral delivery of these compounds difficult.
Given the beneficial nature of these compounds, it is desirable to find methods of delivery that would allow for larger quantities to be consumed, or would provide for the use of catechin-based flavonoids in contexts in which they are not normally found, potentially providing increased consumption and/or exposure to the catechin-based flavonoids, thereby increasing the potential to receive the pharmacological benefit of these compounds.